Lead-exposed Rat Research Articles

Folic acid alleviates lead acetate-mediated cardiotoxicity by down-regulating the expression levels of Nrf2, HO-1, GRP78, and CHOP proteins.

The purpose of this study was to explore the interventional effects of folic acid on the heart damage caused by lead acetate exposure. Twenty-four 60-day-old male Sprague-Dawley (SD) rats were randomly divided into 4 groups with 6 rats in each group. The control group (C group) was normal rats; the lead exposure group (L group) rats drank 0.2% lead acetate solution freely for 14days. The rats in the intervention group (T group) were given 0.2% lead acetate solution for 14days, respectively, and 0.4mg/kg BW folic acid solution was given to the rats by gavage on the 7th day of lead administration. The rats in the folic acid group (group E) were given 0.4mg/kg BW folic acid solution by gavage. To weigh rat body weight and heart weight, calculate heart index, and observe the expression level of nuclear factor erythroid 2-related factor 2(Nrf2), heme oxygenase 1(HO-1), glucose-regulated protein 78/binding immunoglobulin protein (GRP78), and C/EBP-homologous protein (CHOP) by immunofluorescence method. The results showed that compared with group C, serum lead levels in group L and T were significantly increased (P < 0.05); superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) levels in group L were significantly decreased (P < 0.05), and malondialdehyde (MDA) content was significantly higher increased (P < 0.05), and the GSH-PX content in group T were significantly increased in group L (P < 0.05), and the MDA content in group T was significantly lower than that in group L (P < 0.05). Compared with group C, the expression of Nrf2, HO-1, GRP78, and CHOP in group L increased significantly, and the difference was statistically significant (P < 0.05). Compared with the L group, the expression of Nrf2, HO-1, GRP78, and CHOP in the T group was reduced. Therefore, folic acid has a certain protective effect on the oxidative damage of lead-exposed rat heart tissue. Lead exposure will increase ROS, NO, MDA, and other oxidizing substances and reduce the level of GSH, SOD, CAT, GPx, and other antioxidant factors, which will lead to cardiac hypertrophy, cardiac index increase, oxidative stress, Nrf2, and HO-1. The expression of stress-related proteins such as GRP78 and CHOP also increased, leading to cardiomyocyte apoptosis. After a folic acid intervention, these changes can be significantly reversed.

Neuroprotective effects of vitamin C and garlic on glycoconjugates changes of cerebellar cortex in lead-exposed rat offspring

The deteriorating effects of Lead (Pb) on central nervous system (CNS) such as cerebellum has been demonstrated in previous studies. Glycoconjugates with the important role in CNS development may be affected by Pb-exposure. Utilization of antioxidant agents and herbal plants has attracted a great deal of attention on attenuating neurotoxicants-induced damage. Thus, in this study the neuroprotective effects of vitamin C and garlic on content of glycoconjugates of cerebellar cortex in Pb-exposed animals were investigated. Wistar pregnant rats were divided into: control (C), Pb-exposed (Pb) (1500 ppm lead acetate in drinking water), Pb plus vitamin C (Pb + Vit C) (500 mg/kg) intraperitoneally, Pb plus garlic (Pb + G) (1 mL /100 g body weight fresh garlic juice via gavage), Pb plus vitamin C and garlic (Pb + Vit C + G), and sham groups (Sh). Finally, levels of Pb in blood were measured in both rats and offspring on postnatal day 50 (PND50). Also, the cerebellums were removed for measuring Pb-levels and performing lectin histochemistry. Blood and cerebellar Pb-levels were increased in Pb-exposed group compared to control group (P < 0.001), whereas they were decreased significantly in Pb + Vit C, Pb + G, and Pb + Vit C + G groups (P < 0.01). By using MPA, UEA-1, and WGA lectin histochemistry, Pb-exposed group showed weak staining intensity compared to other groups. Besides, significant decrease was observed in the density of lectin-positive neurons of Pb-exposed group compared to the control group (P < 0.001). Moreover, strong staining intensity and high lectin-positive neurons were found in Pb + Vit C, Pb + G and Pb + Vit C + G groups than Pb-exposed group (P < 0.001). The present study revealed that Pb-exposure can result in alteration in the cerebellar glycoconjugates contents and co-administration of vitamin C and garlic could attenuate the adverse effects of Pb. The findings of this study revealed the ameliorating effects of vitamin C and garlic against Pb, suggesting the potential use of vitamin C and garlic as preventive agents in Pb poisoning.

Effects of Ascorbic Acid on Osteopontin Expression and Axonal Myelination in the Developing Cerebellum of Lead-Exposed Rat Pups.

Osteopontin (OPN) is a multi-functional protein that binds to integrin and calcium-binding phosphoprotein. OPN is required for normal neuronal development and its axonal myelination. We studied the combined effect of lead (Pb) and ascorbic acid treatment on OPN expression in the developing cerebellum. We randomly divided pregnant female rats into three groups: control, Pb (lead acetate, 0.3%, drinking water), and Pb plus ascorbic acid (PA; ascorbic acid, 100 mg/kg, oral intubation) groups. The blood level of Pb was significantly increased, while ascorbic acid reduced Pb levels in the dams and pups. At postnatal day (PND) 21, results from Nissl staining and OPN immunohistochemistry demonstrated that OPN was detected in the Purkinje cell layer in the cerebellum. Ascorbic acid treatment mitigated Pb exposure-induced reduction in the number of intact Purkinje cells and OPN immunoreactive Purkinje cells in the cerebellum of pups. In addition, Pb-induced reduction in the number of oligodendrocytes and myelin-associated glycoprotein is associated with the malformation of the myelin sheath. Ascorbic acid provided protection from Pb-induced impairments. Pb-induced structural deficits in the cerebellum resulted in functional deterioration observed during locomotive tests (bar holding test and wire mesh ascending test), while ascorbic acid ameliorated these harmful effects. Present results suggest that the change of OPN is associated with myelination in the developing cerebellum. The results also demonstrated that exposure to Pb is harmful, while ascorbic acid treatment is beneficial.

Dietary grape seed procyanidin extract protects against lead-induced heart injury in rats involving endoplasmic reticulum stress inhibition and AKT activation

To investigate the protective role of grape seed procyanidin extract (GSPE) against lead-induced heart injury and the possible molecular mechanism associated with this event, Wistar rats were orally given GSPE (200 mg/kg) daily with or without lead acetate (PbA) (0.5 g/L) in drinking water for 56 d. GSPE attenuated oxidative stress, heart dysfunction, and lead accumulation in lead-exposed rat hearts. Meanwhile, GSPE inhibited the protein kinase RNA-like endoplasmic reticulum (ER) kinase/eukaryotic initiation factor 2α signaling pathway, and promoted protein kinase B (AKT) and glycogen synthase kinase 3β phosphorylation altered by lead, and regulated lead-activated apoptosis and its related signaling pathway. This study suggests that dietary GSPE ameliorates lead-induced heart injury associated with ER stress inhibition and AKT activation. Dietary GSPE may be a protector against lead-induced heart injury and a novel therapy for lead exposure.

EFFECT OF LEAD ON MALE REPRODUCTION IN EXPERIMENTAL ANIMAL MODEL

Introduction: In early 1960's, there is a first evidence of the toxic effects ionizing radiation on elevated oxygen levels in aerobes and proposed that oxygen toxicity is due to free radical formation. An alteration between oxidants and antioxidants in favour of the oxidants, potentially leading to damage is termed 'oxidative stress'. Lead and cadmium do not have any detectable beneficial biological roles rather it produces detrimental effects on biochemical, physiological and behavioral dysfunctions. Even a little lead poisoning can cause serious health problems, and at very high levels, it can be fatal. Mainly it affects the heamopoeitc system, Liver, Kidney, Cardiovascular system and reproductive system. Methodology: Experimental rats, injected intraperitoneally with lead acetate for 15 days at the dosage of 50, 100 mg/kg/day body weight and compared to control rats injected with deionized distilled water instead. At the end of study testis were removed and right testis was used for testicular antioxidant Malandealdehyde (MDA) levels estimation by Thiobarbituric acid reactive substance assay and left testis was used for histopathological analysis. Unpaired t test and ANOVA was used for statistical analysis. Results : The MDA (nmole /gm tissue) levels in control, lead 50mg, lead 100mg groups were 12.16±0.4, 17.06±0.16 and 18.11±0.13. Histopathology examination Lumen showing decreased sperm count and maturation. Some of the lumens showing absence sperm maturation. Conclusion: Study on lead-exposed rat testis have shown that reduction of spermatogenesis formation and sperm maturation. Increased MDA levels indicate that it may be due to oxidative stress. The toxicity of lead was noted at level ≥50mg/kg. Key words: Lead; Lipid peroxidation; Male reproduction; Testicular histology.

L-Ascorbic Acid and Alpha-Tocopherol Supplementation and Antioxidant Status in Nickel-or Lead-Exposed Rat Brain Tissue

We evaluated the effect of L-ascorbic acid and alpha-tocopherol supplementation on plasma and whole brain nitric oxide level and antioxidant status in nickel sulfate- or lead acetate- treated male albino rats. Nitric oxide and lipid peroxide levels in whole brain tissue and plasma increased following nickel and lead treatment but significantly returned to near-normal values upon L-ascorbic acid or alpha-tocopherol supplementation. In brain tissue, antioxidant enzymes--superoxide dismutase, glutathione peroxidase, glutathione peroxidase, and catalase--along with the glutathione level decreased significantly after both treatments but significantly improved upon simultaneous supplementation with L-ascorbic acid or alpha-tocopherol. Lead-treated animals showed a greater improvement with alpha-tocopherol, whereas nickel-treated rats showed a greater improvement with L-ascorbic acid. In both groups, combined supplementation with L-ascorbic acid and alpha-tocopherol did not change the percentage improvement in comparison with supplementation with a single vitamin alone.

Protection effects of S-adenosyl-L-methionine on lead-exposed rats during development and its mechanism of long-term potentiation

To explore the effects of S-adenosyl-L-methionine (SAM) on blood lead concentration and oxidative stress of tissue in prenatal and postnatal lead-exposed rats, and evaluate the potential reparation exerted by SAM on paired-pulse facilitation (PPF) and long-term potentiation (LTP) in lead-exposed rat. Pregnant Wistar rats were randomly divided into three groups: control, lead-exposed and lead-exposed with SAM treatment groups. Lead-exposed rats drank 1.5 g/L lead acetate solution through pregnancy until weaning and then the pups received 20 mg/kg SAM or saline daily intraperitoneally depending on their group. Control group rats drank tap water throughout the experiment. At the postnatal 44-60 days, all the pup rats were given an extracellular recording measured in dentate gyrus (DG) area of hippocampus. The blood lead concentration and oxidative stress in liver, brain and hippocampus were also detected. The blood lead concentration in lead-exposed group was higher (159. 3 +/- 10. 9 microg/L) in comparing with those of control group (27.5 +/-3.8 microg/L) and lead +SAM group (33.1 +/-9.5 microg/L) (F=213.5, P<0.01). A significant recovery of liver, brain glutathione (GSH) and malondialdehyde (MDA) level was clearly produced in lead-exposed rats after SAM treatment (P <0.05). Chronic lead exposure during development impaired LTP measured on field excitatory postsynaptic potential (EPSP) [(112 +/-2.1)%] compared with control rats [(131+/-4.5)%] and the impaired LTP could be significantly increased by SAM treatment [(120 +/- 2.6)%] (F = 26. 1, P <0. 05). SAM might be beneficial for treatment of lead intoxication, especially in the rescue of learning and memory impairment induced by lead and should deserve more detailed research.

?-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

To understanding the reversible or irreversible harm to the beta-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain beta-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and beta-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of beta-adrenergic receptor using the ligand [125I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain beta-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the beta-adrenergic system of the brain is a partly reversible condition.

BONE LEAD LEVELS IN RELATION TO BASELINE PULSE PRESSURE: THE NORMATIVE AGING STUDY

ISEE-368 Background: The lead-exposed rat demonstrates increased vascular reactive oxygen species (ROS), and blood lead level has been positively correlated with increased plasma markers of oxidative stress in humans. ROS contribute to vascular pathophysiology, one manifestation of which is an increase in the pulse pressure [the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP)]. We hypothesized that lead exposure might predict pulse pressure in humans. Methods: In a substudy of the Normative Aging Study, a longitudinal cohort of male veterans, we measured participants' bone lead level using K-shell x-ray fluorescence and blood pressure using standard mercury sphygmomanometry. Subjects were included if they had satisfactory bone lead and blood pressure determinations and were excluded if they were taking antihypertensives. A total of 598 men, aged 48-93, met these criteria. Using simple and multiple linear regression, we computed the difference in pulse pressure associated with progressively higher levels of bone lead. We could not assume a linear association between bone lead and pulse pressure, therefore we examined bone lead in quintiles. Results: The mean levels of tibia lead among the first through the fifth quintiles were 7.4, 14.1, 18.9, 24.9, and 40.8 micrograms per gram, respectively. Pulse pressure ranged from 21 to 95 mm Hg with a mean of 53 mm Hg. In unadjusted analyses, tibia lead levels were positively associated with SBP and negatively associated with DBP. Higher tibia lead level was associated with progressively higher pulse pressure after adjusting for age, age squared, family history of hypertension, fasting plasma glucose, and alcohol intake. Compared with the pulse pressure of men in the lowest quintile of tibia lead, the mean differences in pulse pressure in the second through the fifth quintiles, respectively, were -2.7, -0.08, 2.56, 3.25, p value for trend 0.006. Conclusion: We found that bone lead level independently predicted pulse pressure. This is consistent with lead exposure contributing to ROS mediated vascular pathophysiology. This finding may shed light on previous work in which the positive association of lead with SBP and the negative association of lead with DBP were interpreted as inconsistent.

Nitric oxide affects LTP in area CA1 and CA3 of hippocampus in low-level lead-exposed rat.

Neonatal Wistar rats were exposed to lead from parturition to weaning via the milk of dams drinking 0.2% lead acetate solution. The alterations in EPSPs in areas CA1 and CA3 of hippocampal slices of 60-day-old adult rats following developmental lead exposure were studied. The results demonstrate that lead exposure in neonatal rats causes a decrease in LTP in area CA1 and an increase in LTP in area CA3. The effects of exposure to NO-generating compound sodium nitroprusside (SNP) on LTP in areas CA1 and CA3 of control and lead-exposed rats were also tested. The data demonstrate that NO causes an increase in LTP in area CA1 and no different alterations in area CA3 of lead-exposed rats. The results also demonstrate that NO may be a messenger molecule in areas CA1 and CA3. It suggests that lead might selectively interfere with specific neurochemical pathways in the hippocampus.

Assessment of slow axonal transport in lead-exposed rats

To evaluate the effect of lead on slow axonal transport, mean transport velocity (Vmean) of radiolabeled proteins in the motor fibers of the sciatic nerve was calculated by simulating the distribution of radioactivity along the nerve 2 weeks after intraspinal injection of L-[35S] methionine in eight rats given drinking water containing lead acetate for 13 weeks. The transport of individual radiolabeled proteins was also inspected visually by fluorography. It was observed that the Vmean was significantly slowed in the lead-exposed rats and was correlated with blood lead concentration; fluorography indicated that the transport of neurofilament proteins and of tubulins was mildly retarded in the most severely affected lead-exposed rat. These findings suggest that slow axonal transport was impaired by lead. Further study using a large number of animals will be necessary to confirm the findings of the present study.

The renal handling of δ-aminolevulinic acid in the rat and in the human

Renal mechanisms for handling δ-aminolevulinic acid (ALA) were investigated in control and lead-exposed rat and human populations. Elevated plasma ALA levels consequent to lead exposure permitted study of these mechanisms under conditions of heavy load. Reabsorption was observed in both species. The reabsorption mechanism appears to be saturable in the human and exists in parallel with a secretory process of smaller capacity. Reabsorption in the rat has a much larger capacity than in the human but appears also to be saturable. No secretory mechanism was apparent in the rat.